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Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):690-701
Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma
Man Chun John Ma,1* Saber Tadros,1* Alyssa Bouska,2 Tayla Heavican,2 Haopeng Yang,1 Qing Deng,1 Dalia Moore,3 Ariz Akhter,4 Keenan Hartert,3 Neeraj Jain,1 Jordan Showell,1 Sreejoyee Ghosh,1 Lesley Street,5 Marta Davidson,5 Christopher Carey,6 Joshua Tobin,7 Deepak Perumal,8 Julie M. Vose,9 Matthew A. Lunning,9 Aliyah R. Sohani,10 Benjamin J. Chen,11 Shannon Buckley,12 Loretta J. Nastoupil,1 R. Eric Davis,1 Jason R. Westin,1 Nathan H. Fowler,1 Samir Parekh,8 Maher Gandhi,7 Sattva Neelapu,1 Douglas Stewart,5 Kapil Bhalla,13 Javeed Iqbal,2 Timothy Greiner,2 Scott J. Rodig,14 Adnan Mansoor5 and Michael R. Green1,14,15
1Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; 3Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; 5Section of Hematology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 6Northern Institute for Research, Newcastle University, Newcastle upon Tyne, UK; 7Diamantina Institute, University of Queensland, Queensland, Australia; 8Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 9Department of Internal Medicine, Division of Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE, USA; 10Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 11Department of Pathology, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, MA, USA; 12Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA; 13Department of Pathology, Brigham and Womens Hospital, Boston, MA, USA; 14Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA and 15Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
*MCJM and ST contributed equally as co-first authors.
ABSTRACT
B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clin- ically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL sub- types have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genom- ic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to dis- ease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL sub- types and a framework of co-occurring genetic alterations that deregu- late genetic hallmarks and likely cooperate in lymphomagenesis.
Non-Hodgkin Lymphoma
Correspondence:
MICHAEL R. GREEN
mgreen5@mdanderson.org
Received: October 16, 2020. Accepted: March 15, 2021. Pre-published: April 1, 2021.
https://doi.org/10.3324/haematol.2020.274258 ©2022 Ferrata Storti Foundation
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